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Lung cancer represents the most common cause of cancer death in both men and women in the United States. Non-small cell lung cancer (NSCLC) occurs much more commonly than small cell lung cancer, accounting for approximately 80% of total lung cancer cases.

Approximately 40% of patients diagnosed with NSCLC present with advanced disease (stage IIIB with pleural effusion or stage IV).

Platinum-based chemotherapy doublets are generally delivered as first-line treatment to patients with advanced NSCLC, with the intent of improving overall survival as well as palliating symptoms.

Epidermal growth factor (EGFR) is expressed in over 80% of NSCLC tumors, and overexpression is associated with poor prognosis, tumor growth, and increased risk of metastasis.

Overall survival benefit with addition of cetuximab to either conventional chemotherapy or radiotherapy in colorectal and head and neck cancers has been demonstrated in phase III trials (Hebbar 2007; Bonner 2006).

A previous randomized phase II FLEX (First-Line Treatment for Patients with EGFR-EXpressing Advanced NSCLC)trial compared cisplatin and vinorelbine to cisplatin, vinorelbine, and cetuximab in patients with advanced NSCLC. Forty-three patients were randomized to each arm. Improvement in outcomes were seen with the addition of cetuximab; tumor response was improved from 28% to 35% with addition of cetuximab, progression-free survival was improved from 4.6 months to 5 months, and overall survival was improved from 7.3 to 8.3 months (Rosell, 2008).

Data from the FLEX phase II trial prompted the design of the FLEX phase III trial, the results from which are presented here. This trial represents a phase III, randomized, controlled trial designed to determine overall survival benefit with addition of cetuximab to cisplatin/ vinorelbine.

Materials and Methods

Patients were randomized to one of two arms as part of this trial. The reference arm consisted of cisplatin (80 mg/ m2 on day 1) and vinorelbine (25 mg/l m2 on days 1 and 8) given every three weeks (CV). The experimental arm consisted of the same regimen, with the addition of cetuximab (400 mg/ m2 followed by 250 mg/ m2 weekly) (CV + C). Following a maximum of 6 cycles of chemotherapy, patients from either arm continued on maintenance cetuxiumab until progressive disease or drug intolerance developed.

Of note, vinorelbine dosing was originally planned to be 30 mg/m2. This dose was reduced to 25 mg/ m2 due to hematologic toxicity after enrollment began.

The trial was designed to have 90% power to detect a significant difference in overall survival; the trial was intended to randomize 1100 patients.

Patient stratification was performed according to ECOG performance status and tumor stage.

Two interim safety analyses were planned.

Eligibility criteria included stage IIIB disease with pleural effusion (“wet” IIIB) or stage IV disease, NSCLC of any histology, ECOG performance status of 0-2, age of at least 18, and EGFR expression as measured by immunohistochemistry (IHC). Positive EGFR expression was defined as at least one cell staining positive on IHC.

o1125 patients agreed to trial enrollment and randomization. 557 patients were randomized to CV + C and 568 to CV.

·Baseline patient characteristics were well-balanced between the two arms.

oPatients were 70% male, and median age was 59 years.

oTumor histology was adenocarcinoma in 47% of cases, and squamous cell carcinoma in 34%.

oECOG performance status was 2 in approximately 20% of patients treated on both arms.

oThe majority of patients randomized to both arms (94%) had stage IV disease.

oNever smokers composed 22% of patients enrolled on both arms.

·Treatment characteristics outside of the study randomization were also similar between study arms:

oA median of 4 chemotherapy cycles were delivered to patients randomized to both arms, with median treatment duration of 14 weeks.

o80% of the total patients received maintenance cetuximab therapy, with a median course of 18 weeks of cetuximab.

oPost-study treatments consisted of radiotherapy, chemotherapy, and other treatments, and were for the most part similar between arms. The single difference noted in post-study treatment between the two arms was greater use of EGFR-tyrosine kinase inhibitors (EGFR-TKI) in the CV arm. Patients randomized to CV received EGFR-TKI therapy in 27% of cases, versus 17% of patients randomized to CV + C (p < 0.05)

When secondary endpoints were examined, tumor response rate was found to be 36% in patients treated with CV + C versus 29% in those treated with CV (p = 0.012). Progression free survival was 4.8 months in both arms (p = NS). Time to treatment failure was prolonged from 3.7 months to 4.2 months in patients treated with CV + C (p = 0.015).

Safety analysis demonstrated the incidence of any even to be 91% in patients randomized to CV + C, and 86% in those randomized to CV.

Treatment-related death occurred in 3% of patients treated with CV + C, versus 2% of those treated with CV.

Author's Conclusions

The authors conclude that cetuximab added to first-line chemotherapy in treatment of patients with advanced NSCLC and EGFR expression provides a statistically significant increase in overall survival.

They note that side effect profiles were as expected between the two arms.

They specifically note that no definite conclusions could be drawn regarding the benefit of cetuximab in treatment of Asian patients, as the small sample size and variance in baseline and treatment characteristics between the two arms prevented a valid analysis.

They conclude that this trial sets a new standard for first line treatment of patients with advanced NSCLC, and opens new treatment opportunities for patients with earlier-stage disease.

As noted, close to half of patients with newly diagnosed NSCLC present with advanced disease, and treatment options are quite limited for these patients. The OS benefit demonstrated within this study is certainly a promising result, both for patients with advanced NSCLC, and potentially for patients with earlier stage disease.

The authors’ conclusions that this trial sets a new standard for first line treatment of patients with advanced NSCLC, however, should be considered carefully in light of several other factors:

First, the OS benefit provided from the addition of cetuximab to conventional chemotherapy was fairly modest, with cetuximab portending a median survival advantage of 1.2 months.

The economic ramifications of delivering this treatment to all patients with advanced NSCLC should not be underestimated. Although cetuximab is demonstrated in this study to provide a real survival benefit to patients with EGFR expression, the cost to other areas of healthcare from this economic investment must be considered carefully.

Additionally, the group of patients receiving CV + C in this trial had a 22% rate of febrile neutropenia, versus 15% of patients receiving CV. Although this increased rate of febrile neutropenia did not appear to increase sepsis rates, it is considerably higher than rates generally observed with first-line chemotherapy. No clear etiology for this increased risk exists, but will likely require further investigation should this result prove durable across other studies.

Having said this, a statistically significant OS benefit with addition of cetuximab was demonstrated within this study, and this benefit may be more important for certain patient subgroups.

Patients with histologic diagnosis of adenocarcinoma appeared to have improved prognosis at baseline, as well as improved response to cetuximab.

Additionally, patients were selected for inclusion in this trial based on IHC staining for EGFR. Recent data presented by the Southwest Oncology Group suggests that the number of EGFR copies as assessed by fluorescence in-situ hybridization (FISH) may be directly related to response to cetuximab (Hirsch, in press).

As further data with regard to molecular markers becomes available, further elucidation of subsets of patients with increased likelihood of response to cetuximab may become possible; this would certainly be helpful in terms of resource allocation and healthcare economics.

In the meantime, this trial demonstrates a modest but real survival advantage for patients with advanced NSCLC treated with cetuximab added to conventional chemotherapy versus chemotherapy alone. This data is interesting and supports findings in head and neck and colorectal cancer that cetuximab is effective and safe when utilized concurrently with conventional chemotherapy.

These findings are clinically important, and are an important contribution to the literature regarding treatment of patients with NSCLC.